Cholesterol suppresses GOLM1-dependent selective autophagy of RTKs in hepatocellular carcinoma

Cell Rep. 2022 Apr 19;39(3):110712. doi: 10.1016/j.celrep.2022.110712.

Abstract

Aberrant activation of receptor tyrosine kinases (RTKs) and the subsequent metabolic reprogramming play critical roles in cancer progression. Our previous study has shown that Golgi membrane protein 1 (GOLM1) promotes hepatocellular carcinoma (HCC) metastasis by enhancing the recycling of RTKs. However, how this RTK recycling process is regulated and coupled with RTK degradation remains poorly defined. Here, we demonstrate that cholesterol suppresses the autophagic degradation of RTKs in a GOLM1-dependent manner. Further mechanistic studies reveal that GOLM1 mediates the selective autophagy of RTKs by interacting with LC3 through an LC3-interacting region (LIR), which is regulated by a cholesterol-mTORC1 axis. Lowering cholesterol by statins improves the efficacy of multiple tyrosine kinase inhibitors (TKIs) in vivo. Our findings indicate that cholesterol serves as a signal to switch GOLM1-RTK degradation to GOLM1-RTK recycling and suggest that lowering cholesterol by statin may be a promising combination strategy to improve the TKI efficiency in HCC.

Keywords: CP: Cancer; CP: Cell biology; cholesterol metabolism; liver cancer; lysosomal degradation; statin; tyrosine kinase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autophagy
  • Carcinoma, Hepatocellular* / pathology
  • Cholesterol
  • Humans
  • Liver Neoplasms* / pathology
  • Membrane Proteins / metabolism
  • Receptor Protein-Tyrosine Kinases

Substances

  • GOLM1 protein, human
  • Membrane Proteins
  • Cholesterol
  • Receptor Protein-Tyrosine Kinases